POLITAG-M-F as Heterogeneous Organocatalyst for the Waste-Minimized Synthesis of β-Azido Carbonyl Compounds in Batch and under Flow Conditions

We herein report a waste minimization protocol for the β-azidation of α,β-unsaturated carbonyl compounds using TMSN3. The selection of the appropriate catalyst (POLITAG-M-F), in combination with the reaction medium, resulted in enhanced catalytic efficiency and a low environmental footprint. The thermal and mechanical stability of the polymeric support allowed us to recover the POLITAG-M-F catalyst for up to 10 consecutive runs. The CH3CN:H2O azeotrope has a 2-fold positive effect on the process, increasing the efficiency of the protocol and minimizing waste generation. Indeed, the azeotropic mixture, used as a reaction medium and for the workup procedure, was recovered by distillation, leading to an easy and environmentally friendly procedure for product isolation in high yield and with a low E-factor. A comprehensive evaluation of the environmental profile was performed by the calculation of different green metrics (AE, RME, MRP, 1/SF) and a comparison with other literature available protocols. A flow protocol was defined to scale-up the process, and up to 65 mmol of substrates were efficiently converted with a productivity of 0.3 mmol/min.


General Remarks
4-Vinylbenzylchloride (VBC) and styrene (STY) were extracted three times with a 10% w/w NaOH solution and filtered through Al2O3 pad to remove the polymerization inhibitor (tertbutyl catechol). Dibenzoylperoxide was re-crystallized from methanol. Trimethylsilyl azide (97% pure, d: 0.860 Kg/L) and β-azido ketones were purchased from Sigma-Aldrich, Alfa Aesar and TCI. GLC analyses were performed by using Agilent 5890 Series II GC System equipped with a capillary column DB-5MS (30 m, 0.32 mm), a FID detector and helium as gas carrier. GC-EIMS analyses were carried out by using a Hewlett-Packard HP 6890N Network GC system/5975 Mass Selective Detector equipped with an electron impact ionizer at 70 eV. All 1 H-NMR, 13 C-NMR spectra were recorded on a Bruker DRX-ADVANCE 400 MHz ( 1 H at 400 MHz and 13 C at 100.6 MHz) using a convenient deuterated solvent (CDCl3). Chemical shifts are reported in ppm (δ) and coupling constants (J) in Hertz and multiplicity are reported as follows: s = singlet, bs = broad singlet, d = doublet, dd = double doublet, td = double triplet, t = triplet, m = multiplet. Spectra are reported considering the product purity >95%. Thin Layer Cromatography analyses were performed on silica gel on silica plates and UV and/or KMnO4 were used as revealing systems.
Characterization data and copies of the 1 H and 13 C NMR spectra of the compounds are reported below.
Caution! All the procedures should be carried out in a fume hood wearing personal protective equipment. Detailed information regarding the safety hazards of all chemicals should be obtained from the Safety Data Sheets (SDS).
The resulting SP02-Cl resins were dried under vacuum for 15 h at room temperature. The amount of Cl on polymer surface was determined by elemental analysis (L: 1.4 mmol/g, Cl: 5.055; M: 3.4 mmol/g, Cl: 12.078).

Synthesis of POLITAGs-I.
A 25 mL two-neck round bottom flask equipped with magnetic stirrer and an argon inlet was charged with 3,3-bis(1H-imidazol-1-yl)propan-1-ol ligand (1.2 eq) in 10 mL of dry DMF. At 0°C NaH (60% in mineral oil; 3 eq) was slowly added and the mixture was kept under stirring for 20 min and for additional 30 min at 28 °C. Then the resin SP02-Cl was added (0.8 g) and the mixture was kept under stirring at 60 °C for 24 h. The resulting material was washed with water and acetone and dried under vacuum. The polymeric material was placed in presence of of 5 mL of MeI and kept under stirring at 90°C. After 20 h the resulting POLITAG-I was filtered and washed with methanol and acetone and dried under vacuum. Loading of bisimidazolium units supported on polymer were determined by elemental analysis (POLITAG-L-I: C: 61.360; N: 3.09; H: 6.366; 0.55 mmol/g ligand loading, 1.1 mmol/g Iloading; POLITAG-M-I: C: 49.32; N: 5.63; H: 5.837; 1.01 mmol/g ligand loading, 2.02 mmol/g Iloading)

Synthesis of POLITAGs-F.
POLITAG-I was charged onto a chromatographic column and an aqueous solution of KF (2M) was passed through the material until no silver iodide precipitate from the eluted solution. After the completion of the ionic exchange the resin was washed with acetone and dried under vacuum. Loading of bis-imidazolium units supported on polymer were determined by elemental analysis (POLITAG-L-F: C: 71.88; N: 3.48; H: 9.878; 0.62 mmol/g ligand loading, 1.24 mmol/g Floading; POLITAG-M-F: C: 68.64; N: 7.43; H: 8.353; 1.33 mmol/g of ligand, 2.66 mmol/g of F -).

Recycle of POLITAG-M-F
The crude reaction mixture was filtered off from the vial and the POLITAG-M-F was washed for 3 times with 1 mL of azeotrope CH3CN:H2O, each time the azeotrope used was filtered off and collected. The POLITAG-M-F was dried at 100°C under vacuum for 3 h and reused without significant mass losses.